tbuckley/cabot-search huggingface dataset:
LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [<sup>177</sup>Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Louise Kathleen Kostos, James Patrick Buteau, Grace Kong, Theresa Yeung, Juliana Di Iulio, Michael T Fahey, Heidi Fettke, Luc Furic, Michael S Hofman, Arun Azad
Journal: Journal of Clinical Oncology (2023)

TPS278 Background: [ 177 Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [ 177 Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [ 177 Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [ 177 Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [ 177 Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [ 177 Lu]Lu-PSMA-617 in combination. Up to 6 doses of [ 177 Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m 2 - 20mg/m 2 ), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [ 177 Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .
Preliminary results from a phase 1/2 study of co-stimulatory bispecific PSMAxCD28 antibody REGN5678 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mark N. Stein, Jingsong Zhang, William Kevin Kelly, David R Wise, Kai Tsao, Benedito A. Carneiro, Gerald Steven Falchook, Furong Sun, Shilpa Govindraj, Jennifer S Sims, Min Zhu, Frank A. Seebach, Israel Lowy, Pradeep Thanigaimani, Sabina Sandigursky, Elizabeth Miller
Journal: Journal of Clinical Oncology (2023)

154 Background: Pts with mCRPC have a poor prognosis with limited treatment options, including minimal response to immunotherapies. REGN5678 is a first-in-class, full-length anti-PSMAxCD28 bispecific costimulatory antibody designed to target prostate cancer cells and enhance T-cell activation. We report preliminary results from the dose escalation part of a first-in-human, open-label, Phase 1/2 study (NCT03972657) examining REGN5678 in combination with cemiplimab, a PD-1 blocking antibody. Methods: Pts with mCRPC had received ≥2 lines of systemic therapy in the metastatic and/or castration-resistant setting, including ≥1 second-generation anti-androgen. Pts received REGN5678 weekly at dose levels [DL] 0.1–300 mg, initially as monotherapy for 3 weeks, followed by combination with cemiplimab (350 mg Q3W) until progression or toxicity. Primary objectives are safety, tolerability, and pharmacokinetics. Preliminary efficacy measurements include decline in prostate-specific antigen (PSA) from the start of combination treatment and radiographic response from baseline. Results: At the data cutoff (DCO; July 27 2022), 35 pts had been treated. Treatment-emergent adverse events (TEAEs) ≥Grade (G)3 occurred in 54% (19/35) of pts. Cytokine release syndrome occurred in 6 pts (all G1) and there were 2 dose-limiting toxicities (both G3): pain (at 1 mg) and Guillain-Barré syndrome (at 300 mg). 4 pts (11%) experienced a ≥G3 immune-mediated adverse event (imAE; at DLs 30–300 mg). REGN5678 exposure was non-linear over the tested DLs (more than dose proportional). There were minimal signs of efficacy at lower DLs (REGN5678 0.1–10 mg), with only 1/16 pts showing a PSA decline (of 21%). More PSA declines occurred at higher DLs: 1/4 pts at 30 mg (a PSA decline of 100%), 3/8 at 100 mg (&gt;99%, 44%, 22%), and 3/4 at 300 mg (&gt;99%, 99%, 82%). Notably, all ≥G3 imAEs occurred in pts with PSA declines. Among pts with measurable disease and ≥1 on-treatment scan, radiographic response per RECIST 1.1 occurred in 1/3 pts at 30 mg (complete response), 1/4 at 100 mg (unconfirmed partial response [PR]), and 1/1 at 300 mg (PR confirmed after DCO). Conclusions: Preliminary data on REGN5678 plus cemiplimab in pts with mCRPC provide first evidence of clinical activity of a CD28 co-stimulatory bispecific antibody in solid tumors. Clinical activity was observed at DLs 30–300 mg. ≥G3 imAEs occurred in pts with PSA declines, suggesting a possible association. The study is ongoing to determine the maximum tolerated and recommended Phase 2 doses. Clinical trial information: NCT03972657 . [Table: see text]
Titration as an effective strategy to reduce apalutamide induced skin rash: A multi-institutional real-world experience.
Authors: Zhixian Yu, Kaiyuan Yu, Shihui Lv, Huihuang Wen, Weijie Fang
Journal: Journal of Clinical Oncology (2023)

197 Background: With increasing use of novel androgen receptor inhibitors to treat prostate cancer (PCa), better safety management has been spotlighted. Apalutamide (APA) is suggested for metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castrate-resistant prostate cancer (NM-CRPC). However, around 25% of patients will experience skin rash. This analysis aims to investigate whether dose titration might be effective to reduce the incidence of skin rash for apalutamide-treated patients. Methods: A retrospective analysis of 73 PCa patients received APA plus androgen deprivation therapy at 3 centers in Wenzhou, China by Aug 2022 was done. Titration was defined as starting APA from a low daily dose of 120mg or 180mg and gradually increase to 240mg. The study group was dose titration patients and compare group was patients received initial 240mg qd. 1 center used 1-week dose escalation (120mg qd in week 1, 180mg qd in week 2, 240mg qd in week 3 and after) strategy and the rest 2 centers used personalized plan (starting dose of 120 or 180mg qd, the physican decide when to increase the dose). Incidence of skin rash, Grade 3 skin rash, dose modification and termination were compared. We also compared the PSA response of two groups at 1,3 and 6 months. Results: 31 and 42 patients in study and control groups were enrolled. Median age was 75.36 years (56.0-90.0), with 1.67 m height (1.50-1.80) and 69.0 kg weight (47.5-92.0). 51% was mHSPC, 90% had Gleason score ≥ 8, 66% have a high tumor volume per CHAARTED. Incidence of skin rash was significantly lower in the study vs control (6.45% vs 26.19%, p=0.029). No patient in study vs 3 (7.5%) patients in control experienced Grade 3 rash. 2 (7.69%) and 9 (22.50%) patients in study and control had dose modification and 3 (7.5%) patients in control group terminated APA due to adverse events. PSA response was slightly lower in study group in month 1 (median PSA decline, study vs control, 85.80% vs 93.85%, p = 0.117) and was consistent in month 3 (95.17% vs 98.71, p=0.152) and month 6 (98.61% vs 99.19%, p=0.530). For selection of titration strategy, incidence of skin rash between 1-week strategy and personalized strategy was consistent (5.88% vs 7.14%, p=0.887). 1-week strategy has significantly better PSA decline at month 1 (median PSA decline, 1-week vs personalized 97.00% vs 75.54%, p=0.019) and performs slightly better in month 3 (99.29% vs 87.74%, p=0.087) vs personalized strategy, in which patients’ dose started to increase between week 2-8. Conclusions: Our results demonstrated that titration might be an effective strategy to reduce incidence of skin rash for PCa patients receiving apalutamide, with little interference to patient efficacy in PSA decline. For time frame to increase dose, 1-week plan might be a better selection. Future prospective studies are needed for validation.
Comparative outcomes of metastatic prostate cancer (mPC) patients (pts) with DNA damage response gene alterations (DDR-a): A single-center experience.
Authors: Khalid Almunaikh, Michael Paul Kolinsky, Naveen S. Basappa, Scott A. North, Sunita Ghosh, Karen Y. Niederhoffer, Soufiane El Hallani
Journal: Journal of Clinical Oncology (2023)

169 Background: DDR-a are prevalent in mPC pts. The clinical behaviour of these pts is not well defined. We sought to investigate how DDR-a affects prognosis and treatment outcomes in mPC pts. Methods: Eligible pts were age ≥18 with mPC who had undergone germline (G) and/or somatic (S) next generation sequencing (NGS) at the Cross Cancer Institute 2016-2021. Pts were considered DDR-a if a pathogenic/likely pathogenic variant (P/LP-v) in a DDR gene was identified on G or S NGS; patients were considered DDR-p if no P/LP-v was identified on S NGS. Data from electronic medical records were collected. The primary endpoint was overall survival (OS) from diagnosis of mPC. Secondary endpoints included: OS and progression free survival (PFS) from initial diagnosis of prostate cancer (PC); PSA response after 12 weeks, and PFS and OS from the start time of 1st and 2nd line therapies. Time based endpoints were analyzed using the Kaplan-Meier (KM) method, and log-rank statistics were used to compare the KM curves. PSA responses were compared using chi-squared testing. Results: 23 DDR-a and 48 DDR-p pts were identified. The most frequent DDR-a were BRCA2 (n=11) and ATM (n=6). Baseline characteristics including age at diagnosis were similar between the two groups. 1st line systemic therapy was androgen deprivation therapy (ADT) alone in 73.9% of DDR-a and 77.0% of DDR-p. 2nd line therapy was abiraterone or enzalutamide in 65% of DDR-a and 92% of DDR-p. Olaparib was received by 52% of DDR-a pts. No difference in OS from mPC (65.7 vs 51.0 mos, p=0.487), OS from initial diagnosis (94.1 vs 88.9 mos, p=0.865), PFS on 1st line therapy (33.2 vs 31.0 mos, p=0.847), OS on 1st line therapy (85.6 vs 78.6 mos, (p=0.799) PFS on 2nd line therapy (8.4 vs 13.1 mos, p=0.569) or OS on 2nd line therapy (32.5 vs 35.8 mos, p=0.901) was seen for DDR-a vs DDR-p, respectively. PSA responses to 1st and 2nd line therapies were similar and will be presented as waterfall plots. Conclusions: In this single-center cohort, no difference in clinical characteristics or outcomes were seen in DDR-a compared to DDR-p pts. While this study is limited by small numbers and retrospective nature, it adds to the growing literature characterizing the clinical behaviour of DDR-a mPC. Collaborative efforts are required to better define this molecular cohort of pts.
Differences in concomitant medication prescribing before and after novel hormonal therapy (NHT) in men with prostate cancer: A population-based study.
Authors: Amy Yang, Chuchu Mei, Joshua Banks, Nikita Nikita, Amy L Shaver, Scott W. Keith, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2023)

138 Background: Prostate cancer (PCa) is the most common non-skin cancer affecting American men. Two common NHTs used to treat PCa are enzalutamide and abiraterone. Due to the different mechanisms of these two NHTs, we hypothesized that the concomitant medications prescribed might be related to therapy-related adverse effects. The purpose of this study was to examine whether changes in concomitant medications depended on the NHT prescribed. Methods: Medicare patients with a prescription of either enzalutamide or abiraterone in the Surveillance, Epidemiology, and End Results (SEER)–Medicare database diagnosed with prostate cancer from January 01, 2004 to December 31, 2015 were included. Medications were classified by Lexicomp’s pharmacologic category. Only oral prescriptions were included. McNemar’s test was used to compare the drug use prevalence of each category prior to and after initiation of NHT. Generalized logistic regression was used to evaluate whether changes in prescription drug class during the 6 months post-NHT initiation periods depended on the type of NHT. Results: Among the 1067 patients included, 354 were prescribed enzalutamide and 713 were prescribed abiraterone. We found statistically significant interactions between NHT (enzalutamide vs. abiraterone) and period (post vs. preinitiation NHT). Patients prescribed enzalutamide were more likely to discontinue prescriptions for steroids (p&lt;0.01) as expected. The odds of fluoroquinolones, non-steroidal anti-inflammatory drugs (NSAIDs), and loop diuretics prescriptions were similar pre-NHT initiation for both enzalutamide and abiraterone patients; however, patients treated with enzalutamide were significantly less likely than abiraterone patients to have post-NHT initiation prescriptions for fluoroquinolones (Odds ratio (OR) 0.69 p=0.01) or loop diuretics (OR: 0.57 p&lt;0.01). Conclusions: To our knowledge, this is the first population-based study to describe concurrent medication prescribing before and after NHT. Further studies are warranted to better understand the underlying reasons for the observed patterns.
Developing a novel patient-reported outcome measure for patients with prostate cancer receiving radionuclide therapy: The FACT-RNT.
Authors: Lisa M. Gudenkauf, Melody Chavez, Melinda Maconi, Carley Geiss, Ameen Seyedroudbari, Pan Thin, Aasha Hoogland, Kathleen Nguyen, Laura B. Oswald, Heather S.L. Jim, Ghassan El-Haddad, Wolfgang Peter Fendler, Ken Herrmann, David Cella, Johannes Czernin, Michael S Hofman, Adam P. Dicker, Jeremie Calais, Scott T. Tagawa, Brian D. Gonzalez
Journal: Journal of Clinical Oncology (2023)

130 Background: The field of targeted radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly with recent FDA approval of the first lutetium-177-PSMA-ligand. Commonly used patient-reported outcome (PRO) measures were originally designed to assess the impacts of traditional therapies (e.g., chemotherapy, surgery). We aimed to develop the first PRO measure for PC patients receiving RNT. Methods: We used a multi-step approach based on input from experts and patients. We identified symptoms and toxicities potentially relevant in the context of RNT for PC from a literature review of published trials and interviews with PC patients who had received RNT, caregivers of RNT recipients, and clinicians. We identified items to include in the measure from the Functional Assessment of Chronic Illness Therapy (FACIT) item library. Finally, we reviewed, refined, and finalized the new measure. Results: Potentially relevant symptoms/toxicities were identified by reviewing published trials (e.g., xerostomia, nausea). Interviews with PC patients who received RNT (n=29), caregivers (n=14), and clinicians (n=11) yielded additional symptoms/toxicities (e.g., fatigue, constipation). After selecting a broad and comprehensive list of items from the FACIT item library, we refined the list based on input from 9 experts in the field of RNTs and PROs from 5 institutions. Patients who received RNT for PC (n=11) reviewed the draft measure and confirmed items were relevant to RNT recipients and comprehensible. This resulted in a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusions: The FACT-RNT (Functional Assessment of Cancer Therapy – Radionuclide Therapy) is a PRO new measure for RNT recipients developed through multi-step collaboration with patients, caregivers, clinicians, and international experts. The FACT-RNT can be used in RNT clinical trials and real-world settings.
Phase 1/2a study of PRL-02, a long-acting intramuscular (IM) depot injection of abiraterone decanoate in patients (pts) with advanced prostate cancer.
Authors: Jose W. Avitia, Ronald F. Tutrone, Neal D. Shore, James L. Bailen, Luke T. Nordquist, William Richardson, Cody J. Peer, William Douglas Figg, Jacqueline M. Walling, Joel Robert Eisner, Matthew Sharp, Robert Schotzinger, William R. Moore
Journal: Journal of Clinical Oncology (2023)

141 Background: PRL-02 (abiraterone decanoate) is a novel, long-acting IM depot prodrug of abiraterone. In non-clinical models, PRL-02 provided high and durable concentrations of prodrug and abiraterone to target tissues including adrenal glands, lymph nodes and bone. Single doses of PRL-02 suppressed testosterone (T) through 14 weeks in a castrate monkey model to concentrations comparable to oral abiraterone acetate (AA) with lower and less variable plasma abiraterone exposures. Clinically, PRL-02 blocks androgens with minimal increases in mineralocorticoids or depletion of glucocorticoids via inhibition of CYP17 lyase and minimal inhibition of CYP17 hydroxylase. PRL-02 has the potential for a superior therapeutic index and safety profile compared to oral AA. Methods: Phase 1 is a standard 3+3 design intended to identify a recommended phase 2 dose (RP2D). Pts with metastatic castrate resistant or sensitive prostate cancer (mCRPC/mCSPC) and a screening T of 2 - 50 ng/dL were administered IM PRL-02 every 12 weeks with daily oral dexamethasone. Results: As of 8Sep22, 17 pts (6 mCRPC, 11 mCSPC) were treated across 5 dose cohorts (180, 360, 720, 1260, 1800mg). Generally, there was a dose-proportional increase in abiraterone concentrations following a single dose of PRL-02 with a Tmax of 14 - 28 days and a plasma half-life of 18.3 days. The median baseline T level was 7.45ng/dL. Among pts dosed at 720mg and above, 9 of 11 had a 90% reduction in T or values ≤ 1ng/dL at day 28, including 2 pts with T≤LLOQ of 0.1 ng/dL, and PSA50 responses were observed in 8 of 10 with post-baseline results. There were no treatment related serious adverse events (AEs) or dose limiting toxicities. G3 AEs related to PRL-02 included hip and shoulder pain. G2 related AEs included fatigue, decreased appetite, insomnia and hot flush; symptoms of mineralocorticoid excess were not reported. Minimal and transient changes in ‘up-stream’ steroids (e.g., progesterone (P) and corticosterone (C)) were observed through the 1800mg dose. Although serial radiology was not prospectively required, there was radiographic improvement in 6 pts with data available. Conclusions: PRL-02 was well tolerated. Dose-dependent T suppression was associated with clinical benefit including PSA responses and radiographic improvement. Based on a historical comparison, the levels of P and C are significantly lower than seen with AA + prednisone which appear to be due to greater CYP17 lyase selectivity. The 1260mg or 1800mg dose will be the RP2D. Clinical trial information: NCT04729114 . [Table: see text]
A phase II trial modifying metabolic syndrome and cardiovascular risk for patients with prostate cancer on ADT using a risk factor modification program and continuous Fitbit monitoring (ProTrio).
Authors: Andrew Warren Hahn, Rebecca Slack Tidwell, Whittney Thoman, Amer Abdulla, Efstratios Koutroumpakis, Ana Aparicio, Sumit Kumar Subudhi, Bilal Ahmed Siddiqui, Patrick Glen Pilié, Amado J. Zurita, Paul Gettys Corn, Andrew Leonard Laccetti, Bagi RP Jana, Karen Basen-Engquist, Christopher Logothetis
Journal: Journal of Clinical Oncology (2023)

TPS273 Background: Prostate cancer is a disease of older age, and there is significant overlap with age-related illnesses. Androgens play a critical role in prostate cancer but also have been linked to cardiovascular (CV) disease, metabolic syndrome, bone health, and frailty. ADT is associated with an increased risk of CV events primarily due to increased rates of diabetes, dyslipidemia, and adverse changes in body composition. We assume that prostate cancer and age-related illnesses share biology with therapeutic implications in a subset of men. The ProTrio trial will test the hypothesis that a 16-week digital risk factor modification program will improve 10-year atherosclerotic cardiovascular disease (ASCVD) risk score as compared to usual care in men with potentially lethal prostate cancer receiving ADT. Methods: This single center, open-label, randomized phase II trial is evaluating a 16-week digital risk factor modification program, which includes an exercise prescription (150 minutes of titrated cardiovascular exercise and resistance exercise 2 times a week) with support via a smart phone application (Moving Analytics) and Fitbit, in patients with prostate cancer who are receiving ADT compared to usual care with Fitbit monitoring. Eligible patients are men receiving ADT +/- an androgen signaling inhibitor for at least 3 months prior to enrollment. The study will enroll to two cohorts: (1) distant metastatic disease and (2) biochemically recurrent or regional lymph node disease. Patients will be stratified according to their baseline ASCVD risk score. The primary endpoint is the difference in ASCVD risk score post-intervention. Secondary endpoints include difference in metabolic severity index z-score, PSA velocity, 6-minute walk, 5X Sit-to-Stand, body composition, physical activity measured by Fitbit, and health-related quality of life. Up to 100 patients will be enrolled in each cohort. A clinically relevant improvement in ASCVD score reduction is 2.5%. With 44 men per arm, after 12% dropout, we can detect an improvement of 2.5% vs. 0% at a 2-sided 5% significance level with 80% power assuming a standard deviation (SD) of 4.125%. A sample size adjustment is planned based on the SD of the first cohort to reach 44 patients. Each cohort will undergo futility analysis once half the men are enrolled. The study is enrolling at MD Anderson Cancer Center. Clinical trial information: NCT05054296 .